Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

Summary The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (1.5mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-³H-glucose turnover were 20–25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41±4 vs 8±6 mol·min^–1·kg^–1. p < 0.001) but did not further decrease 3-³H-glucose turnover. Elevated nonesterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability. Increased glycogen synthesis, however, compensates for decreased glycolytic flux so that glucose turnover is not decreased. When liver glycogen stores are high, an acute increase in non-esterified fatty acid availability impairs suppression of hepatic glucose output. A chronic increase in non-esteriefid fatty acid availability may lead to insulin resistance by increasing glycogen stores.     

Carbohydrate metabolism in pregnancy XVI: Longitudinal estimates of the effects of pregnancy on D-(63H) glucose and D-(6-14C) glucose turnovers during fasting in the rat

We measured blood glucose concentrations and glucose turnover rates in 24 hr fasted, conscious, unrestrained pregnant rats and nongravid controls on days 18, 19, and 20 of gestation. Turnover measurements were secured with simultaneous equilibrium infusions of D-(6-³H) and D-(6-¹⁴C) glucose so that gluconeogenic recycling could also be determined. “Steady state” values for blood glucose in the mother after 24 hr of fasting did not significantly differ on each of the days, and these concentrations were significantly lower than the values in 24 hr fasted nongravid rats. At 18 days gestation, glucose turnover did not differ from nongravid values. By contrast, values for glucose turnover after 24 hr fasting increased significantly and progressively in the 19 and 20 day pregnant rats. The increase in turnover correlated with the increasing growth of the conceptus. The ratio between D-(6-¹⁴C) glucose and D-(6-³H) turnover remained constant (and the same as in the nongravid rats) during all 3 days of gestation suggesting that rates of glucose recycling remained unaltered. These longitudinal studies indicate that the factors contributing to the pattern of “accelerated starvation” during dietary deprivation in pregnancy may vary as pregnancy progresses. The exaggerated lowering of blood glucose which accompanies fasting occurs before total glucose turnover increases. This could provide a potential mechanism for conserving maternal glucose. Since transplacental transfer of glucose is concentration-dependent, the early establishment of a lower “steady state” for circulating glucose could diminish the magnitude of loss of this key nutrient to the fetus.     

In vivo demonstration of nitrogen-sparing mechanisms for glucose and amino acids in the injured rat

Changes in protein metabolism 8 hr after anesthesia and femur fracture were studied in healthy rats fasted or receiving either intravenous glucose or crystalline amino acids. Whole body rates of amino acid turnover (flux) and release from protein (breakdown) as well as fractional synthetic rates of mixed muscle, liver, and plasma protein were measured using the constant infusion of L-(I-¹⁴C)-leucine. Injury resulted in a 24% and 63% increase in the synthesis of liver (p < 0.05) and plasma proteins (p < 0.01), respectively. Amino acid infusions in the injured animals further increased the synthesis of liver protein (from 36.6% to 44.3%/day, p < 0.05) and increased muscle protein synthesis (from 7.0% to 9.3%/day, p < 0.05) without altering rates of protein breakdown. Glucose infusions, in contrast, reduced whole body protein breakdown 36% (p < 0.05) when compared to fasting, and depleted the plasma essential amino acid pool (p < 0.05). The usual increases in liver protein synthesis observed in fasted rats following injury were not seen when the animals were receiving intravenous glucose. The nitrogen-sparing mechanism of these two infusions are different. Protein-free glucose infusions impair the normal response to injury aimed at increasing visceral protein synthesis and maintaining plasma essential amino acid concentrations.     

Effect of feeding a high-fat diet during pregnancy on glucose metabolism in the rat

To alter glucose homeostasis in a period of great glucose demand, pregnant rats were submitted to a high-fat diet and compared to virgin rats. In virgin rats, blood glucose, ketone bodies, plasma insulin, and free fatty acids were not affected by the diet consumed. Glucose turnover measured in the postabsorptive period was slightly decreased in virgin rats fed a high-fat diet compared to rats fed a standard diet. Assuming that the glucose turnover rate is representative for the 24-hour average endogenous glucose production, in rats fed a standard diet the daily carbohydrate intake (9.2 +/- 0.7 g/d) exceeded the glucose turnover rate (4 +/- 0.2 g/d) and could meet the glucose requirement. In rats fed a high-fat diet the carbohydrate intake (2.7 +/- 0.2 g/d) was lower than the glucose turnover rate (3.8 +/- 0.2 g/d), which demonstrated the need for an active endogenous glucose production. Blood glucose, ketone bodies, plasma insulin, and free fatty acid concentrations followed the same patterns during pregnancy in rats fed a standard diet compared to rats fed a high-fat diet. The glucose turnover rate in the postabsorptive period was no more decreased by the high-fat diet in pregnant rats compared to virgin rats despite the greater glucose demand. In late pregnancy the glucose turnover rate was increased up to 70%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in liver nucleic acids and nucleotides in arginine deficient rats

Dietary arginine deficiency is associated with retarded growth and depressed feed intake. Nucleic acid biosynthesis as indicated by the incorporation of [6-¹⁴C]-orotic acid and [³²p]-orthophosphate was significantly depressed in rats fed an arginine deficient diet. The activities of the pyrimidine enzymes, aspartate transcarbamylase (ATC) and dihydroorotate dehydrogenase (DHODH) were significantly increased in rats fed an arginine deficient diet. ATC and DHODH activities in rats fed the arginine deficient diet returned to control activities after 3 wk of feeding. Orotidine 5′ phosphate decarboxylase and orotate phosphoribosyl transferase activities were not affected by dietary arginine availability. In the rat fed an arginine deficient diet there was an increase in total liver pyrimidine nucleotides and a decrease in the total purine nucleotides. Significant alterations in the individual liver nucleotides were also observed. Incubation of various tissues obtained from rats fed an arginine deficient diet or a complete diet with glutamine (5mM) revealed that the liver is the major site of orotic acid synthesis. Orotic acid production in liver slices using glutamine as the nitrogen source was significantly greater in rats fed an arginine deficient diet compared to controls. The orotic aciduria occurring in rats fed an arginine deficient diet is associated with increased synthesis and decreased utilization of pyrimidines.     

Relationship of plasma leucine and α-ketoisocaproate during a L-[1-13C]leucine infusion in man: A method for measuring human intracellular leucine tracer enrichment

The keto analog of leucine, α-ketoisocaproate (KIC), is formed intracellularly from leucine and is released, in part, into the systemic circulation. Therefore, KIC can be used to estimate intracellular leucine tracer enrichment in man during labeled-leucine tracer experiments without requiring tissue biopsy samples. This approach was studied in young, healthy, male adults maintained on different dietary protein intakes from generous (1.5 g kg^?1d^?1) to deficient (0.0 g kg^?1d^?1) for 5–7 day periods. At the end of each dietary period, the volunteers were given a primed, continuous infusion of L-[1-¹³C]leucine either after an overnight fast (postabsorptive state) or while being fed hourly aliquots of the same diet. The plasma concentrations of all 3 branched-chain amino and keto acid pairs were measured from early morning blood samples taken from 4 subjects at 4 different levels of protein intake. Leucine concentration showed a weak correlation, and valine concentration showed a strong correlation with protein intake; isoleucine and the 3 keto acids did not. However, each branched-chain amino acid concentration was strongly correlated with its corresponding keto acid concentration. In plasma samples obtained during the L-[1-¹³C]leucine infusions, the ratio of [1-¹³C]KIC to [1-¹³C]leucine enrichment ratio remained relatively constant (77 ± 1% over the wide range of dietary protein intakes and for both the fed and postabsorptive states. For the tissues from which the plasma KIC originates, the rate of plasma leucine into cells will account for approximately 77% of the intracellular leucine flux with the remaining 23% coming primarily from leucine release via protein breakdown. The constant nature of the plasma KIC to leucine ¹³C enrichment ratio implies that relative changes in leucine kinetics will appear the same under many dietary circumstances regardless of whether plasma leucine or KIC enrichments are used for the calculations.     

THE HYPOGLYCAEMIC ACTION OF SOMATOSTATIN IN THE ANAESTHETIZED DOG

The hypoglycaemic action of somatostatin was investigated in fasted anaesthetized dogs. An isotopic turnover technique with radioactive D-[2-³H] glucose tracer was used to measure the rats of hepatic production and peripheral utilization of glucose before, during, and after a 60 min infusion of 150 μg somatostatin. Plasma concentrations of insulin, glucagon, growth hormone, cortisol and free fatty acids were also measured. Somatostatin infusion caused a fall of plasma glucose demonstrable within 10 min. After 60 min plasma glucose had fallen to 75% of the pre-infusion concentration. Simultaneously the specific activity of the D-[2-³H] glucose increased and calculation of the rates of production and utilization of glucose over 10 min intervals indicated that the mean hepatic production rate of glucose fell to 59% of the pre-infusion rate while the rate of peripheral utilization of glucose fell to 83% of the pre-infusion rate. These results show that the hypoglycaemic action of intravenous somatostatin depends exclusively upon the inhibition of hepatic glucose production. This effect may have been partly due to a fall of plasma glucagon concentration and occurred despite a fall of plasma insulin to less than 1 mu 1^-1.     

The effect of enteric galactose on neonatal canine carbohydrate metabolism

Newborn pups were assigned to a fasting group or to a group receiving intravenous glucose alimentation. Glucose turnover was determined during steady state equilibration of simultaneously infused [6-³H] glucose. Thereafter, pups from each group received 0.625 g/Kg of either oral [U-¹⁴C] galactose or [U-¹⁴C] glucose. In fasted or intravenously alimented pups enteric glucose resulted in a rapid and sustained elevation of blood glucose concentrations. Systemic appearance of carbon-14 label from enteric glucose increased rapidly as did the enrichment of blood [¹⁴C] glucose specific activity. In those pups given enteric galactose, blood glucose values were equivalent to that in the glucose fed groups, however carbon-14 appearing in blood glucose and blood glucose specific activity were significantly lower. The peak values for the rates of appearance and disappearance of systemic glucose were significantly lower in pups fed galactose than among pups fed glucose. Glucose clearance was also significantly lower in these pups despite equivalent plasma insulin responses. Among fasting pups hepatic glycogen content was significantly higher in those given either oral glucose or galactose when compared to a completely starved control group. In contrast, among alimented pups galactose administration significantly enhanced hepatic glycogen content compared to those fed glucose. Similarly, enteric substrate label incorporation into hepatic glycogen was enhanced in both groups given oral labeled galactose. In addition, hepatic glycogen synthase (glucose-6-phosphate independent) activity was increased only among alimented pups fed galactose when compared to completely fasted pups. In conclusion these data suggest that following gastrointestinal galactose administration, hepatic carbohydrate uptake is augmented while glycogen synthesis may be enhanced. Augmented glycogen synthesis following galactose administration may reflect alterations in hepatic glycogen synthase activity or enhanced hepatic carbohydrate uptake.     

The effect of bovine insulin on [14C]glucose and [3H]leucine incorporation in fed and fasted rainbow trout (Salmo gairdneri)

The effect of bovine insulin on tissue incorporation of [¹⁴C]glucose and [³H]leucine was investigated in fed and fasted rainbow trout reared on a control and high-protein diet. Insulin produced marked hypoglycemia and mobilization of liver glycogen in all treatments. Although insulin gave no evidence of glycogenic stimulation it did appear to promote oxidative clearance of [¹⁴C]glucose. Compared to [¹⁴C]glucose much greater tissue incorporation of [³H]leucine was observed in fasted fish; insulin stimulated the incorporation of [³H]leucine into skeletal muscle protein. In plasma, liver, and skeletal muscle of all treatments, the summed specific activities of [³H]leucine was considerably greater than that of the summed values of [¹⁴C]glucose following insulin administration. Four weeks of fasting apparently lowered basal metabolism but no changes were observed in plasma glucose and glycogen stores. There was some evidence of gluconeogenic activity in the high protein-fasted fish and the data indicated in all fasted treatments a stimulation of [¹⁴C]glucose and [³H]leucine metabolism following insulin administration.     

Influence of nicotinic acid on the rates of turnover and oxidation of plasma glucose in man

The effects of antilipolysis induced by nicotinic acid on the rates of turnover and oxidation of plasma glucose were studied in normal overnight fasted, obese overnight fasted, and obese starved subjects, using a ¹⁴C-glucose infusion technique. Changes induced by nicotinic acid were similar whatever the nutritional state of the subjects. Plasma FFA levels and blood concentrations of glycerol and ketones decreased by about 60%; glycemia remained essentially unchanged but both the removal rate of plasma glucose and the hepatic glucose output increased by about 25%. Moreover, the fraction of glucose taken up by tissues and promptly oxidized and the fraction of expired CO₂ derived from plasma glucose increased, respectively, by 18% and 33%. This enhancement of glucose utilization occurred despite a small but significant decrease in plasma IRI concentration, indicating that nicotinic acid increased sensitivity to insulin. The above-mentioned results were obtained in 8 of the 10 patients studied. The remaining two subjects did not respond to the administration of nicotinic acid by any significant decrease in FFA nor in glycerol concentrations and showed no change in the rates of glucose turnover and oxidation. These data indicate that the effects of nicotinic acid on glucose metabolism may be partly mediated through changes in plasma FFA concentration and are consistent with the idea that the “glucose-fatty acid cycle” plays a significant role in the control of glucose metabolism in man.     

Fatty acid metabolism in the heart during Escherichia coli sepsis in the rat

Fatty acid metabolism was studied in fasted control, fasted Escherichia coli-treated, fed control, and fed E. coli-treated rats to find out whether the reduction in myocardial carnitine was associated with changes in oxidation and esterification of long chain fatty acids. Rats were made septic by injecting i.v. 8 X 10(7) live colonies of E. coli per 100 g body weight. Fed rats were infused intragastrically with a nutritionally adequate diet containing glucose plus fat for five days before inducing sepsis. Food was removed from the fasted rats after E. coli injection. Twenty-four hours later, the production of CO2 from [1-14C]palmitate was not altered in heart homogenates from fasted or fed E. coli-treated rats. In comparison to control rats, heart homogenates from fasted E. coli-treated rats incorporated 32% more [1-14C]palmitate into triglycerides. The heart content of triglycerides was also increased threefold during sepsis. Rates of esterification and lipid composition were not altered in the hearts from fed E. coli-treated rats. The increased rate of triglyceride synthesis in the hearts from fasted E. coli-treated rats appears to be due to a 40% higher content of glycerol 3-phosphate and 55% more activity of glycerol 3-phosphate acyltransferase. These results also suggest that the reduced content of myocardial carnitine that occurs during E. coli sepsis does not limit the availability of fatty acids for oxidation.     

Increase of microsomal glucose-6-phosphatase activity after chronic ethanol administration

To study the effect of chronic ethanol administration on the activity of hepatic microsomal glucose-6-phosphatase, female rats were pair-fed liquid diets with 36% of total calories either as ethanol or isocaloric carbohydrate (controls). The remainder of the diet contained 35% of total calories as fat, 18% as protein, and 11% as additional carbohydrate. Six weeks of ethanol feeding as isocaloric substitution for carbohydrate increased significantly the activity of glucose-6-phosphatase (expressed per mg microsomal protein) both in fed (38%; p < 0.001) and fasted 18%; p < 0.02) rats. When expressed per unit of body weight, the enzyme activity was increased even further both in fed (66%; p < 0.01) and fasted (43%; p < 0.01) rats. Another group of rats received diets containing 36% of calories either as ethanol or isocaloric fat. The remainder of the diet contained 11% of total calories as carbohydrate, 18% as protein, and 35% as additional fat. Six weeks of this ethanol feeding as isocaloric substitution for fat again increased glucose-6-phosphatase activity significantly. Ultracentrifugation in a Cs⁺-containing sucrose gradient to separate rough and smooth microsomes revealed that the increase in glucose-6-phosphatase activity after ethanol feeding occurred mainly in the smooth microsomal membranes.     

Hexose metabolism in pancreatic islets

Islets from fed and 3-day-starved rats were incubated for 60 min in the presence of either 2.8 or 16.7 mM d-glucose, mixed with tracer amounts ofd-[5-³H]glucose,d-[3,4-¹⁴C]glucose,d-[6-¹⁴C]glucose andd-[2-¹⁴C]glucose. Starvation decreased the generation of³HOH fromd-[5-³H]glucose and the production of¹⁴CO₂ from¹⁴C-labelledd-glucose, both at low and high hexose concentrations. In islets from starved and fed rats, a rise ind-glucose concentration preferentially stimulated oxidative glycolysis, pyruvate decarboxylation and acetyl residue oxidation, relative tod-glucose utilization. At both low and high hexose concentrations and in both fed and starved rats, the decarboxylation of pyruvate exceeded the oxidation of glucose-derived acetyl residues, the C₁ of such residues being more efficiently converted to¹⁴CO₂ than their C₂. Starvation decreased oxidative glycolysis more severely than non-oxidative glycolysis, impaired the preferential stimulation ofd-[3,4-¹⁴C]glucose oxidation relative tod-[5-³H]glucose utilization as observed in response to a rise in hexose concentration, and lowered the ratio betweend-[6-¹⁴C]glucose oxidation and hexose utilization. It is proposed, therefore, that the short-term regulation of mitochondrial oxidative events byd-glucose is itself modulated in islet cells by the nutritional status.     

Persistence of metabolic effects after long-term oral feeding of a structured triglyceride derived from medium-chain triglyceride and fish oil in burned and normal rats

The persistence of metabolic effects following long-term oral feeding of a structured triglyceride rich in omega-3 fatty acids was studied in burned and normal rats, and compared with controls fed safflower oil, a long-chain triglyceride high in omega-6 fatty acid content. Male Sprague-Dawley rats were pair-fed a high fat diet as either structured triglyceride or safflower oil for 42 days. On day 43, a jugular catheter was placed, and rats received either a dorsal surface scald or sham injury. Following a 48-hour fast, body weight, nitrogen loss, energy metabolism, and liver weight were measured, and whole-body and tissue-specific protein kinetics were studied by constant intravenous infusion of [1-14C]leucine. Plasma albumin, free fatty acids, glucose, insulin, and triglyceride fatty acid composition were determined. Urinary nitrogen loss, energy expenditure, and plasma leucine concentration were elevated in burned rats, confirming the presence of an injury response. Rats previously fed structured triglyceride had greater liver weight, total liver protein, and percentage of leucine flux oxidized, and plasma levels of glucose and insulin were increased. Plasma leucine concentration was decreased in rats previously fed structured triglyceride. Plasma triglyceride and phospholipid fatty acid analysis showed a reduction in arachidonic acid and an increase in omega-3 fatty acids in rats previously fed structured triglyceride. Long-term feeding of structured triglyceride induced major systemic metabolic changes related to the dietary fatty acid composition that persist after the diet is discontinued.     

Insulin determines leptin responses during a glucose challenge in fed and fasted rats

OBJECTIVE: Leptin secretion has been shown to respond acutely to changes in blood glucose and insulin. Nutritional state also has a marked effect on both the level of circulating leptin protein and leptin gene expression. The aim of this study was to assess whether the prior nutritional state altered the leptin secretory response to an acute glucose challenge, and to determine potential mechanisms. DESIGN: Male fed or fasted rats (200-250 g) were administered a single intravenous glucose bolus (1, 4 or 7 g/kg). The serum leptin, glucose, insulin and free fatty acid responses were studied over the following 5 h. The level of leptin gene expression and leptin protein was then determined in the epididymal fat pads, and in fed and fasted untreated rats for basal comparison. RESULTS: Leptin secretion in response to glucose was suppressed in fasted rats following all glucose doses. The total leptin response was correlated with the total insulin response in all conditions (r = 0.85) and with the glucose response in fed rats (r = 0.69). Both leptin gene expression and leptin protein content were lower in basal fasted rats. Leptin gene expression and leptin protein content still remained lower 5 h following a glucose bolus but there was partial reversal of the effects of fasting following the 7 g/kg glucose dose. CONCLUSIONS: Leptin secretion in response to an intravenous glucose bolus was determined by the insulin response and was significantly suppressed in fasted compared to fed rats. In addition to differences in the total insulin response of the animals, lower leptin responses may be facilitated by lower levels of both leptin gene mRNA and pre-existing leptin protein in epididymal adipose tissue of fasted rats.     

Oxidation and ketogenesis in hepatocytes of lean and obese Zucker rats

Ketone body production and oxidation of ¹⁴C fatty acids to CO₂ were measured in hepatocytes isolated from lean and obese Zucker rats. The oxidation of [1-¹⁴C]octanoate, [1-¹⁴C]palmitate and [1-¹⁴C]palmitoyl carnitine to ¹⁴CO₂ was 50%–70% less in obese than in lean rats. Although ketone body production in hepatocytes from both lean and obese rats was increased by fasting, there was a significantly lower rate of ketone body production in hepatocytes from obese rats. Ketone body production was reduced to a comparable extent by increasing the glucose concentration in the incubation media of hepatocytes from both lean and obese rats. Glucagon and carnitine increased ketogenesis and the effects were additive and similar in lean and obese rats. These data suggest that β-oxidation and ketogenesis are suppressed in the obese Zucker rat, and further that ketone bodies can be modulated similarly in hepatocytes from lean and obese rats by nutritional and hormonal intervention. It is postulated that the decreased β-oxidation and ketone body production may play a role in the development or maintenance of obesity in the Zucker rat.     

Medium‐chain fatty acids ameliorate insulin resistance caused by high‐fat diets in rats

Background High dietary intake of saturated fat impairs insulin sensitivity and lipid metabolism. The influence of fatty acid chain length, however, is not yet fully understood, but evidence exists for different effects of saturated long‐chain (LC) versus saturated medium‐chain (MC) fatty acids (FA). Methods To investigate the effects of the FA chain length, male Wistar rats were fed high‐fat diets containing triacylglycerols composed of either MC‐ or LCFA for 4 weeks; rats fed maintenance diet served as a control. The animals underwent euglycemic hyperinsulinemic clamping or oral metabolic tolerance testing respectively; enzyme activities of mitochondrial (EC2.3.1.21 carnitine palmitoyl transferase) and peroxisomal (EC1.3.3.6 acyl‐CoA oxidase) FA oxidation were measured in liver and muscle. Results LCFA consumption resulted in higher fasted serum insulin and glucose concentrations compared to controls, while MCFA‐fed animals did not differ from controls. Insulin sensitivity was reduced by 30% in the LCFA group while the MCFA group did not differ from controls. Feeding MCFA resulted in the controls' lowered fasted and post‐prandial triacylglycerol concentration compared to LCFA, while triacylglycerol concentrations in muscle were higher in both high‐fat groups compared to controls. No diet‐induced changes were found in acyl‐CoA oxidase (ACO) activity (liver and muscle), while LCFA feeding significantly raised carnitine palmitoyltransferase activity. Conclusions The chain length of saturated fatty acids in isocaloric diets affects insulin sensitivity, lipid metabolism and mitochondrial fatty acid oxidation without influencing body weight. While dietary LCFA clearly impair insulin sensitivity and lipid metabolism, MCFA seem to protect from lipotoxicity and subsequent insulin resistance without caloric restriction. Copyright © 2009 John Wiley & Sons, Ltd.     

Initial splanchnic extraction of ingested glucose in normal man

Estimates of initial splanchnic uptake of ingested glucose and the concomitant suppression of endogenous glucose production were obtained in man by validated tracer techniques for non-steady-state turnover measurement. Nine normal volunteers (18–44 yr old) fasted overnight received intravenous infusions of tracer (3-³H-glucose or 1-¹⁴C-glucose) and a low (45 ± 1 g) or high (96 ± 5 g) oral load of glucose labeled with an alternative tracer (1-¹⁴C-glucose or 2-³H-glucose). A two-compartment model was used to derive rates of peripheral appearance (Ra) of glucose from all sources (total) and the Ra of ingested glucose. Ra (total glucose) and Ra (ingested glucose) were integrated from the first appearance of ingested glucose until the basal Ra (total glucose) of 116 ± 6 (SEM) mg/min was reattained. The total amount of glucose reaching the systemic pool in this time was 95 ± 4 g and 46 ± 3 g with high and low doses, respectively. Of these quantities 86 ± 4 g and 40 ± 3 g originated in the oral glucose, representing 90% ± 4% of the administered glucose. The remainder (11% ± 2% of the total) represented endogenous production, suppressed by 66% ± 6% relative to basal. Sequestration of ingested glucose and subsequent release did not take place during the study since identical results were obtained with ingested 1-¹⁴C-glucose or 2-³H-glucose. The latter label would have been lost if the glucose had entered the hexose-phosphate pool. Thus, in normal man approximately 90% of an ingested glucose load is absorbed and passes through the liver to appear in the systemic pool.     

Metabolic changes in rats fed a low protein diet during post-weaning growth

Metabolic changes in rats fed a low protein diet were investigated during 3 weeks after weaning using lactalbumin (LP) as dietary protein source. The energy intake was higher and the weight gain lower in rats fed the low protein diet (6%, LP group) than in control rats (13% lactalbumin, C group). Low protein diet induced no changes in plasma glucose, free fatty acids, or triacylglycerol concentrations; however, plasma protein and urea concentrations were lower in LP than in C rats. Plasma free T3 was higher in LP than in C rats (+38%, day 21) and insulin progressively decreased during the experimental period (-56%, day 21) without change in glucagon. Liver glycogen and triacylglycerol concentrations (+40% and +180%, respectively, day 21), and cytosolic and mitochondrial redox states increased (+100% and +100%, day 21), and protein concentration was decreased (-15%, day 21). Pyruvate kinase (PK) and malic enzyme activities were higher in LP than in C rats throughout the experiment (+80% and +210%, respectively, day 21), and glucose-6-phosphate dehydrogenase (G6PDH) activity progressively decreased (-65%, day 21). Phosphoenolpyruvate carboxykinase (PEPCK) activity increased after 2 weeks on a LP diet (+35%, day 21) and fatty acid synthetase (FAS) activity increased only during the first week on the diet (+100%, day 7). Such hormonal and metabolic changes appeared to be associated with the development of a futile energy-wasting cycle between pyruvate and phosphoenolpyruvate.     

Hepatic and very low-density lipoprotein fatty acids in obese offspring of overfed dams

The combined effects of developmental programming and high-fat feeding at weaning on fatty acid metabolism of the offspring are not well known. In the present study, we aim at characterizing the influence of maternal and offspring's own diets on liver and very low-density lipoprotein (VLDL) lipids; fatty acid profiles of VLDL and liver phospholipids, triglycerides, and cholesteryl esters; and hepatic enzyme activities. Twenty obese male rats born to cafeteria diet–fed dams and 20 control rats born to control diet–fed dams were selected. At weaning, 10 rats of each group were fed control or cafeteria diet. Obese rats had a significant increase in serum glucose, insulin, leptin, VLDL apolipoprotein B100 and lipid levels, and hepatic fatty acid synthase and a reduction in acyl–coenzyme A oxidase and dehydrogenase activities compared with control pups at day 21 and day 90. Hepatic steatosis was apparent only at day 90. The proportions of saturated fatty acids and monounsaturated fatty acids and the oleic to stearic acid ratio were significantly increased, whereas polyunsaturated fatty acids and the arachidonic to linoleic acid ratio were decreased, in liver and VLDL lipids of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal cafeteria diet induced a permanent reduction in hepatic β-oxidation and an increase in hepatic lipogenesis that caused liver steatosis and VLDL and fatty acid alterations in adult offspring. These preexisting alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Nutritional recommendations in obesity must then target maternal and postnatal nutrition, especially fatty acid composition.